Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. Here we describe KZR-8445, a cyclic depsipeptide that targets the Sec61 translocon and selectively disrupts secretory and membrane protein biogenesis in a signal peptide-dependent manner. KZR-8445 potently inhibits the secretion of pro-inflammatory cytokines in primary immune cells and is highly efficacious in a mouse model of rheumatoid arthritis. A cryogenic electron microscopy structure reveals that KZR-8445 occupies the fully opened Se61 lateral gate and blocks access to the lumenal plug domain. KZR-8445 binding stabilizes the lateral gate helices in a manner that traps select signal peptides in the Sec61 channel and prevents their movement into the lipid bilayer. Our results establish a framework for the structure-guided discovery of novel therapeutics that selectively modulate Sec61-mediated protein biogenesis.

阻止疾病相关蛋白质的生物发生是一种有吸引力的治疗策略，但针对必需蛋白质生物发生因子的尝试因过度毒性而受到阻碍。在这里，我们描述了 KZR-8445，一种环状缩酚酸肽，它靶向 Sec61 易位子，并以信号肽依赖性方式选择性破坏分泌蛋白和膜蛋白的生物合成。KZR-8445 有效抑制初级免疫细胞中促炎细胞因子的分泌，并且在类风湿性关节炎小鼠模型中非常有效。低温电子显微镜结构显示，KZR-8445 占据完全打开的 Se61 侧门并阻止进入腔塞结构域。KZR-8445 结合以捕获 Sec61 通道中选定信号肽的方式稳定侧门螺旋，并阻止它们移动到脂质双层中。我们的结果建立了一个框架，用于以结构为导向发现选择性调节 Sec61 介导的蛋白质生物合成的新型疗法。